Prenatal phthalate exposure is associated with changes to the placental transcriptome

Abstract

Background: Phthalates disrupt processes involved in placental physiology and fetal development and are associated with a variety of adverse health outcomes in infants and children. The goal of this study was to identify associations between prenatal phthalate exposure and the placental transcriptome. Methods: Maternal urine was collected during the third trimester and placental tissue was collected at delivery from 404 women enrolled in the CANDLE study (Shelby County Tennessee, USA). Sample analyses were conducted by the ECHO PATHWAYS Consortium. 15 phthalate urinary metabolites were quantified using high-performance liquid chromatography-mass spectrometry. Placental transcriptomic data was generated using paired-end RNA sequencing. Linear models were fit using limma-voom to identify associations between each phthalate metabolite (independent variable) and each gene (dependent variable). We used models adjusted only for sequencing batch and models fully adjusted for confounders: maternal education; race and age; sequencing batch; fetal sex; and labor type. Genes were considered statistically significant at a Benjamini-Hochberg false discovery rate (FDR) <0.05. For pathway overrepresentation analysis, we included genes significantly associated with phthalates from minimally adjusted models at an FDR <0.15. Results: We identified 39 pathways associated with one or more of 5/15 phthalates. MMP MBZP, and MBP concentrations were associated with the highest number of genes and pathways. The RIG-1-like receptor signaling pathway, intestinal immune network for IgA production, and the complement and coagulation cascade pathways were enriched for genes associated with multiple phthalates. No genes were statistically significantly associated with urinary phthalate measurements in our fully adjusted model. Conclusion: In this first genome-wide assessment of the third-trimester placental transcriptome, we identified genes associated with phthalate exposure. These genes were related to xenobiotic metabolism, oxidative stress, PPAR signaling, and immune dysregulation, concurrent with phthalates known molecular mechanisms within the placenta. Ongoing work includes collecting additional data and identification of transcriptional regulators.